Comment on "Increased in-hospital mortality from COVID-19 in patients with schizophrenia". Considering the prevalence and protective factors of COVID-19 in patients with schizophrenia.

To the Editor,

We read with great interest the paper by Fond et al. [1] which reports that schizophrenia is not overrepresented among COVID-19 hospitalized patients compared to the prevalence of schizophrenia in the general population. The authors also report that their findings fail to suggest that patients with schizophrenia are more at risk of COVID-19 than the general population, contrary to what could have been expected. We think that this study is clinically important to understand the relationship between schizophrenia and COVID-19 and may contribute to the studies on the pathogenesis of COVID-19 [1]. Therefore, we wish to reveal the possible explanations for the finding of a lower prevalence of COVID-19 in patients with schizophrenia than expected.

Firstly, a higher level of human coronavirus anti-strain antibodies were found in patients with schizophrenia spectrum when compared with non-psychiatric controls [2]. This finding suggests that patients with schizophrenia may have a strong serological response to the coronavirus family including severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). In prenatal and postnatal periods, exposure to several pathogens rather than a single microorganism has been suggested as an aetiological factor for schizophrenia [3], [4]. Hence, acquired serological immunity for several viruses may play a protective role against COVID-19 in patients with schizophrenia.

Schizophrenia susceptibility genes were reported to be implicated in virulence and life cycles of viral pathogens. These genes and their interactions with the immune system and viral pathogens might make patients more resistant to COVID-19. More recently, it has been found a 117-base pair SARS-CoV-2 sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 Orf1b gene. Human NTNG1 encodes a pre-pro-protein which acts to guide axon growth during neuronal development. Polymorphism in this gene has been suggested as a contributing factor to genetic risk for schizophrenia [5], [6].

Another possibility is that increased angiotensin-converting enzyme (ACE) activity reported in patients with schizophrenia may be a protective factor against COVID-19 [7]. ACE converts angiotensin I to angiotensin II. SARS-CoV-2 attaches to ACE II receptor, especially in low pH conditions. Subsequently, it enters the human cell and causes infection. Angiotensin II can produce a high pH even after strong acid loading [8]. Therefore, high angiotensin II levels produced by high ACE activity in patients with schizophrenia may reduce virulence and viral load of SARS-CoV-2 via alkalising effect.

According to the National Institute on Drug Abuse, smoking rate in patients with schizophrenia ranges from 70% to 80%, while it is 19–20% in the general population. Recently, smoking was suggested as a protective factor against COVID-19 in a French study [9]. However, this interesting finding should be replicated and its causality should be confirmed with studies involving larger sample sizes.

In conclusion, patients with schizophrenia should still be considered at high risk for transmission, poor prognosis, and infectivity despite the possibility of COVID-19 being less frequent in these patients. However, the prevalence, protective and predisposing factors of COVID-19 need to be studied in a larger population included hospitalized and non-hospitalized patients to understand true relationship between schizophrenia and COVID-19 and to contribute to the studies on the pathogenesis of COVID-19.

Disclosure of interest

The authors declare that they have no competing interest.

Financial disclosure

The authors declared that this study has received no financial support.